Stimulation of non-motor subthalamic nucleus impairs selective response inhibition via prefrontal connectivity

Abstract Given the inconsistent results in the past, there is an ongoing debate whether and how deep brain stimulation in the subthalamic nucleus modifies cognitive control processes like response inhibition in persons with Parkinson’s disease. In this study, we examined how the location of the stimulation volume within the subthalamic nucleus affects the performance in an antisaccade task but also how its structural connectivity is related to response inhibition. Antisaccade error rates and latencies were collected in 14 participants on and off deep brain stimulation in a randomized order. Stimulation volumes were computed based on patient-specific lead localizations using preoperative MRI and postoperative CT scans. Structural connectivity of the stimulation volumes with pre-defined cortical oculomotor control regions as well as whole-brain connectivity was estimated using a normative connectome. We showed that the detrimental effect of deep brain stimulation on response inhibition, measured as antisaccade error rate, depended upon the magnitude of the intersection of volumes of activated tissue with the non-motor subregion of the subthalamic nucleus and on its structural connectivity with regions of the prefrontal oculomotor network including bilateral frontal eye fields and right anterior cingulate cortex. Our results corroborate previous recommendations for avoidance of stimulation in the ventromedial non-motor subregion of the subthalamic nucleus which connects to the prefrontal cortex to prevent stimulation-induced impulsivity. Furthermore, antisaccades were initiated faster with deep brain stimulation when the stimulation volume was connected to fibres passing the subthalamic nucleus laterally and projecting onto the prefrontal cortex, indicating that improvement of voluntary saccade generation with deep brain stimulation may be an off-target effect driven by stimulation of corticotectal fibres directly projecting from the frontal and supplementary eye fields onto brainstem gaze control areas. Taken together, these findings could help implement individualized circuit-based deep brain stimulation strategies that avoid impulsive side effects while improving voluntary oculomotor control.


Introduction
There is no debate about the effectiveness of deep brain stimulation (DBS) in the subthalamic nucleus (STN) for motor symptoms of Parkinson's disease. Its effects on cognitive and oculomotor functions, on the other hand, remain less clear. Given that the STN has been deemed pivotal for cognitive control processes like response inhibition (i.e. the ability to stop or withhold a reflexive prepotent response), alterations thereof following DBS seem plausible. The results in the literature are yet heterogeneous with studies reporting STN-DBS impairing [1][2][3] or improving response inhibition, 4,5 or leaving it unaltered. [6][7][8] A recent meta-analysis did not confirm an overall detrimental effect of STN-DBS on inhibitory control in Parkinson's disease, 9 so that one may infer differences in task design (global versus selective response inhibition) conditioning these inconsistent findings. 10 Furthermore, analogous to motor symptoms, there could be a differential effect of DBS on cognitive symptoms depending on the extent of the volume of activated tissue (VAT) within the STN and therefore the activated circuitry. 11,12 Best motor symptom control results from stimulation in the dorsolateral 'motor' subregion of the STN which receives projections predominantly from the primary and supplementary motor cortices. [13][14][15] However, despite optimal lead placement and refined DBS programming, VAT may exert effects in ventral and medial portions of the STN and to surrounding structures and fibre tracts, alike. In contrast to the motor subregion, the adjacent ventromedial portions of the STN receive converging cortical projections from prefrontal areas including the pre-supplementary motor area (pre-SMA), the frontal eye field (FEF), dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC); 13 all regions forming an interconnected network involved in response inhibition. 16,17 The exact lead location and VAT within the STN may thus crucially determine effects of DBS on cognitive performance. For instance, DBS of the ventromedial 'associative' subregion of the STN has been related to errors of inhibition, and more broadly with clinically relevant neuropsychiatric symptoms and with DBS-associated cognitive decline. 18,19 The aim of this study was therefore to examine how the position of the VAT in the STN as well as its structural connectivity relates to the individual effect of STN-DBS on response inhibition in Parkinson's disease. To control for DBS-induced improvement in manual responses, we used the antisaccade paradigm, an established response inhibition task in the oculomotor domain. Antisaccades require the selective suppression of a reflexive saccade in the direction of a visual stimulus (the prosaccade) and the execution of a voluntary saccade in the opposite direction instead (the antisaccade) (Fig. 1A). 20 The rate of directional errors towards the visual stimulus serves as proxy for response inhibition capacity, while the latency (i.e. the duration between onset of the visual target and the onset of the saccade) additionally measures the efficiency with which the voluntary action is selected and initiated by the oculomotor control network.
While Parkinson's disease-patients tend to exceed healthy individuals in antisaccade error rates and latencies, 21-23 effects of STN-DBS on antisaccade performance are not fully understood. A recent meta-analysis found an overall decreasing effect of STN-DBS on antisaccade latency but no consistent effect on the rate of directional errors. 24 We hypothesized that inconsistent results of previous studies may be related to variability in the exact location of the DBS lead and the VAT within the STN and its surroundings.

Participants
The study was approved by the Ethical Board of the University Hospital Marburg (reference number 119/19) and followed the Declaration of Helsinki. All participants were recruited from the Movement Disorders Outpatient Clinic of the Department of Neurology at the University Hospital Marburg and gave written informed consent before participation.
A total of 19 subsequent participants with Parkinson's disease diagnosed according to the clinical diagnostic criteria of the Movement Disorders Society 25 treated with STN-DBS participated in this study. Exclusion criteria were (i) mild cognitive impairment or dementia according to the respective MDS task force criteria level 1 and measured with the Montreal Cognitive Assessment (< 24 points), (ii) signs of clinically relevant depression (Beck Depression Inventory > 14 points), (iii) history of any disorder of the central nervous system other than Parkinson's disease, (iv) any concurrent conditions that made eye-tracking impossible (for example, disorders of the eyes or visual system with reduced visual acuity, severe camptocormia and other orthopaedic disorders impairing ability to sit for longer periods) and (v) intake of any medications that may influence eye movements (for example, benzodiazepines).
All participants were in off-medication state after overnight withdrawal of all dopaminergic medication for at least 12 h prior to study assessments.
Five of 19 participants asked for premature discontinuation of the study protocol due to tiredness, discomfort or unbearable motor symptoms in the DBS-off state. Fourteen participants completed at least one block of antisaccade recordings in both conditions and were included in the final analysis.

DBS programming
All patients were implanted bilaterally with leads targeting the sensorimotor part of STN (Vercise Cartesia™ Directional Lead, Boston Scientific Neuromodulation Corporation, Valencia, CA91355, USA). These DBS leads consist of eight contacts configured into two ring contacts at the proximal and distal pole and two three-segment contacts in-between, enabling directionally shaped VAT. 26 The minimum time span between DBS surgery and study inclusion was 3 months to avoid any impact of lesion effects. All participants performed the task twice: with DBS switched off, and in their chronic DBS program that achieved optimal clinical response (Supplementary Table 1). The order of conditions was randomized to avoid bias due to expectations, learning effects or tiredness. The participants were not informed about what changes to their DBS settings were made. The wash-out period between conditions was at least 10 min.

Eye-tracking procedure and analysis
The experiment was programmed in MATLAB 2020b (The Mathworks Inc., Massachusetts, USA) using the psychophysics toolbox (www.psychtoolbox.org) 27 and an infrared video-based eye-tracker (EyeLink 1000 Plus, SR Research, Ontario, Canada) recorded positions of both eyes. Three blocks of 50 horizontal antisaccades in each were presented per condition, resulting in N = 150 trials per condition. Participants were instructed to look at the exact opposite direction of the lateral target stimulus located either 10° left or right from an initial central fixation cue as fast and precisely as possible (Fig. 1A).
After segmentation of the raw pupil position data into visual events (saccades, fixations and blinks) using a parsing system incorporated in the EyeLink 1000 software, the event data set was imported into the statistical computing program R 28 using the Eyelinker package for further analysis (cf. Supplementary Material 1 for detailed description of the eyetracking procedure and analysis).
Antisaccade errors were defined as a saccade towards the lateral stimulus. Saccade latency was defined as the time from stimulus onset to the start of the first saccade. Saccades occurring with very short latency < 90 ms were considered anticipatory and removed from further analysis. The following oculomotor outcome measures were extracted: (i) error rate (proportion of erroneous trials with latency > 89 ms to all valid trials), and (ii) mean latency of correctly executed antisaccades.

Visualization of DBS leads and VAT
Image processing was performed using the pipeline provided in the Lead-DBS software (https://www.lead-dbs.org). 29,30 In brief, pre-operative T2-weighted MRI scans were linearly co-registered to T1-weighted images using SPM12 (http:// www.fil.ion.ucl.ac.uk/spm/software/), and subsequently co-registered to postoperative CT scans using a two-stage linear registration as implemented in Advanced Normalization Tools. 31 The co-registered acquisitions were then spatially normalized into ICBM 2009b NLIN asymmetric standard space 32 using Advanced Normalization Tools. 33 The localizations of DBS leads were corrected for brainshift by applying a refined affine transform calculated between pre-and postoperative acquisitions restricted to a subcortical area of interest. After pre-localization of the DBS electrodes using the PaCER algorithm, 34 their location was manually corrected based on postoperative CT scans using the respective tool as implemented in Lead-DBS software. Consecutively, the orientation of the directional DBS leads was determined using the default algorithm in the package. 35,36 Electrode locations and active contacts were visualized with Lead-Group. 37 Based on the individual DBS settings of each patient, VAT were estimated using a finite element method with an electric field threshold of 0.2 V/mm. 15,29 This model estimated the E-field (i.e. the gradient distribution of the electrical charge in space measured in V/mm) on a tetrahedral mesh that differentiated four compartments (grey and white matter, electrode contacts and insulation) whereby the grey matter structures including a parcellation of the STN subregions were defined using the DISTAL Minimal Atlas. 38 Consecutively, patient-specific VAT were used to calculate their intersection with the motor and non-motor (associative and limbic area combined) subregions of the STN in proportion to total VAT volumes. Finally, these normalized intersection values were averaged between right and left hemisphere for each participant and extracted for further statistical analysis.

Region-of-interest based structural connectivity
The supplementary eye field (SEF), FEF, DLPFC and ACC were selected as a priori regions of interest (ROI) based on their known activation during antisaccades and strong association with antisaccade latency and error rate. [39][40][41][42] The ROI were defined using the Brainnetome atlas 43 as previously used in 44 (Supplementary Table 2). Structural connectivity between VAT and ROI was calculated using a publicly available normative connectome derived from diffusion-weighted MRI of 85 individuals with Parkinson's disease recruited for the Parkinson's Progression Markers Initiative (PPMI, www. ppmi-info.org). 38,45 Regions of interest and patient-specific VAT were projected onto the voxelized volume of the connectome in standard space in 1 mm isotropic resolution. Structural connectivity seeding from the VAT and projecting onto voxels of the respective ROI was estimated for each participant as fibre counts, i.e. numbers of streamlines seeding from VAT.

Whole-brain structural connectivity
To test whether the brain-wide connectivity of the VAT predicted DBS effects on antisaccade measures, we used patient-specific VAT as seed regions to all fibre tracts of the normative connectome. Then, VAT were grouped depending on whether they touched each of the fibres of the connectome or not. The change scores of antisaccade latency, respectively error rate, were compared between connected and unconnected VAT for all fibres using mass t-tests resulting in a t-score for each fibre. Using this approach as previously described by Li and colleagues, 46 a high t-score reflects that a specific fibre is highly explanatory for the DBS effect on the respective oculomotor measure. Only fibres within the 20% highest t-scores, i.e. those with the highest discriminative power, were kept for further statistical analysis.

Statistical analysis
For all analyses, statistical inference was ascertained in R and statistical significance was asserted at α = 0.05. Mean antisaccade latency and error rate were compared on a group level between DBS-off and DBS-on conditions using paired t-tests. Absolute change scores (ΔDBS-on = DBS-off) were calculated for correlation analyses with imaging data so that a negative change score indicates a DBS-induced decrease from DBS-off state values.
Since DBS-induced changes in antisaccade latency and error rate were not expected to be normally distributed, change scores of the oculomotor outcomes were Spearman rankcorrelated with the VAT-STN intersections with the motor and non-motor subregions and with fibre counts connecting the VAT to the pre-defined ROI.
Group-level cross-validation of the derived whole-brain fibre connectivity profiles was performed using a leave-oneout approach. 47 Each patient was excluded once to subsequently re-calculate discriminative fibres based on the fibre connectivity profile generated using the remaining 13 participants. A spatial correlation coefficient was calculated comparing the similarity between the profiles of the single individual with the profile of the remaining cohort. This spatial correlation coefficient was entered into a linear regression model trained on the remaining cohort to predict the individual DBS effects on oculomotor measures of the excluded patient.
For visualization purposes, the strength of structural connectivity was additionally calculated in a voxel-wise manner. Here, the fibre density connecting the VAT with each voxel of the connectome was Spearman rank-correlated with the change in antisaccade latency and error rate across participants. 48 The resulting connectivity maps ('R-maps') represent the Spearman's correlation coefficients in each voxel color-coded for positive and negative correlations.

Data availability
The code for pre-processing of the imaging data, lead localization, VAT generation and connectivity analysis is freely accessible through the Lead-DBS software (www.lead-dbs. org). 29 All newly generated custom-written code for the task (Matlab) and analysis pipelines (R) is available on the following GitHub page: https://github.com/JoWld/PD_ DBS_Antisac. Participants' individual data sets are available upon reasonable request from the corresponding author.

Participants' clinical characteristics
The final analysis resulted from 14 participants (four females) aged of 57.0 ± 8 8 years and with a mean disease duration of 8.6 ± 3.3 years. Mean time between study inclusion and DBS surgery was 10.2 ± 9.1 months. All participants experienced improvement of motor symptom severity when DBS was switched on with a mean relative reduction in MDS-UPDRS III scores of 56.9 ± 21.8%.

Behavioural results
See Table 1 for condition-averaged results.
Paired t-test further revealed no significant effect of condition on antisaccade latency [t(13) = 1.986, P = 0.069] with a mean decrease by 24.0 ± 45.2 ms [95%-CI = (−2.1, 50.1)] in DBS-on condition whereby the confidence interval indicated a trend towards a DBS-induced latency reduction (Fig. 1C). To further visualize the distribution of latencies across trials, the relative latency distributions of all trials are shown colorcoded for condition in Fig. 1D.
Explorative correlations between change scores of oculomotor outcomes and clinical variables (age, disease duration, MoCA score and MDS-UPDRS III change score) were not significant (Supplementary Table 3).

Localization of DBS leads and VAT
See Fig. 2 for the location of all DBS leads in standard space. The bilateral VAT generated by all activated contacts were located to some extent within the STN. Normalized to the total volume of the respective VAT, 51.8 ± 22.6% [range (12.4, 89.0)] of the VAT were localized within the motor

Correlation of antisaccade outcomes and VAT
The normalized VAT intersection with the non-motor subregion of the STN was positively correlated with the change score of antisaccade error rate (ρ = 0.644, P = 0.013). That means that a larger proportion of the VAT localized in the non-motor STN subregion was associated with a larger DBS-induced increase of errors (Fig. 2C, Table 2). Conversely, the change in antisaccade latency was positively correlated with the VAT intersection with the motor subregion of the STN (ρ = 0.736, P = 0.003). That means that a larger proportion of the VAT located in the motor STN subregion was associated with less DBS-induced reduction in antisaccade latency (Fig. 2D).

Structural connectivity with cortical oculomotor network
Considering all fibres connecting the VAT with voxels of the pre-defined ROI in the oculomotor network (Fig. 3), significant positive correlations with the change score of the antisaccade error rate were found for the right ACC (ρ = 0.637, P = 0.014), right FEF (ρ = 0.534, P = 0.025) and left FEF (ρ = 0.595, P = 0.049) (Fig. 4). That means that higher fibre counts connecting the VAT with the right ACC and bilateral FEF were associated with a larger DBS-induced increase in errors. Surprisingly, no such association was found for the DLPFC despite its known key role in the antisaccade task. 49 However, strong correlations between voxels of the right DLPFC and the change in error rate were evident in the whole-brain connectivity map (Fig. 3).
There were no significant correlations of the change score of antisaccade latency with fibre counts connected to the FEF, SEF, DLPFC or ACC (Table 3).

Whole-brain structural connectivity
The whole-brain connectivity maps based on voxel-wise Spearman correlations are displayed in Fig. 3. The wholebrain fibre connectivity profiles are shown for antisaccade error rate in Fig. 5, respectively, for antisaccade latency in Fig. 6.
In the leave-one-out validation, the DBS effect of single individuals on error rate (R = 0.470, P = 0.046) but not latency (R = −0.09, P = 0.375) was predictable by linear models trained on the respective discriminative fibre profiles of the remaining 13 participants. That means that higher similarity of the individual set of discriminative fibres to the group fibre profile correlated with a larger DBS-induced effect on the antisaccade error rate.
Most fibres associated with a larger DBS-induced increase in antisaccade error rate entered the ventromedial portion of STN and projected onto the prefrontal cortex encompassing FEF, SEF and neighbouring areas bilaterally (Fig. 5A-C). In contrast, a smaller proportion of fibres that was associated with a DBS-induced decrease in antisaccade error rate entered the left dorsolateral portion of the STN and projected    more dorsally onto the left prefrontal and motor cortex ( Fig. 5A-C).
Regarding the discriminative fibres for DBS-induced antisaccade latency changes, it became clear that fibre tracts positively or negatively correlated with the change in antisaccade latency differed in their anatomic relation to the STN (Fig. 6). Fibres associated with a DBS-induced decrease in antisaccade latency passed by the STN at its lateral border and projected via the internal capsule onto the superior frontal and pre-central gyrus and downstream to the brainstem and cerebellum potentially consistent with corticotectal, -bulbar and -cerebellar tracts originating from the frontal eye fields and sensorimotor cortex. In a post hoc analysis, the proportion of the VAT localized outside the STN was not predictive for the change in antisaccade latency (ρ = −0.481, P = 0.081), suggesting that the effect was specific for the laterally passing fibres rather than generated by unspecific stimulation of non-STN tissue. Connectivity of the VAT with a smaller proportion of fibres located medial from the first fibre tract was associated with an increase in antisaccade latency with DBS instead. These fibres projected onto the same cortical areas but, in contrast to the first tract, appeared to enter the motor and associative subregions of the STN (Fig. 6).

Summary of findings
In this study, we explored how the exact location of the volume of activated tissue and its structural connectivity affect response inhibition in the antisaccade task in persons with Parkinson's disease treated with DBS in the STN. First, we showed that the DBS effect on antisaccade error rates hinged on the proportion of VAT intersection with the non-motor subregion of the STN and on structural connectivity between the VAT and several prefrontal regions involved in oculomotor control. Further, antisaccade latency tended to decrease in most participants when STN-DBS was switched on. This effect was larger when a 'smaller' portion of the VAT intersected with the motor subregion of the STN, lending credence to the idea that faster initiation of voluntary saccades observed with STN-DBS may relate to stimulation of adjacent structures outside the STN. This interpretation was supported by the identification of two distinct fibre tracts, one traversing the STN, the other one passing the STN laterally, which were associated with differential effects on latency changes.

DBS of non-motor STN regions impairs selective response inhibition
In line with most previous studies, 23,50,51 DBS induced no consistent effect on the rate of antisaccade errors on a group level. According to our data, the detrimental effect on response inhibition observable in some patients with Table 3  STN-DBS might originate from rather ventromedial locations of the VAT within the STN. Another possible source of disinhibition might be the modulation of connections between the VAT and cortical oculomotor control regions such as the FEF and ACC which are involved in the inhibition of reflexive saccades towards the visual target. 42,52,53 Comparable studies investigating the impact of VAT locations on response inhibition are scarce. A previous study exploring effects of DBS amplitude on antisaccades reported that a higher overlap between the VAT and the entire STN was associated with lower antisaccade error rates in the DBS-on state. Further, location of the active DBS contacts outside of the STN was associated with detrimental effects on the error rate. 54 Generalizability may, however, be hampered by small sample sizes for VAT reconstructions, lack of consideration of behavioural changes from DBS-off state and by the fact that subregions within the STN were not differentiated.
Our results may also link to previous reports of activations of different contacts of the same DBS leads on response inhibition. For instance, unilateral stimulation of the most ventral contact impaired performance in a GO/No-go task compared with dorsal stimulation. 55 Conversely, dorsal stimulation improved selective inhibition of conflicting impulses in a Simon task. 56 As such, our findings are in line with these studies supporting deteriorated performance in response inhibition tasks with stimulation in the non-motor subregion of the STN. Conversely, the whole-brain connectivity profile suggests that stimulation of the left motor subregion of the STN may be associated with improved inhibition of antisaccade errors. Given that neurons in the STN activated during saccades tend to be located medial from those involved in manual responses 57 and connections of STN with FEF and SEF are situated medial to those connecting the STN with the pre-SMA, 13 it remains to be determined whether our results are directly transferable to manual response inhibition tasks.
Of note, effects of VAT location may vary in tasks requiring a general stopping of all ongoing actions instead of selective inhibition of a specific reflexive response to allow selection and execution of a voluntary response. For instance, stimulation via ventrally located contacts led to faster stopping times in a stop-signal task. 58 On the same note, Lofredi and colleagues showed that significantly increased stopping times induced by STN-DBS were linked to connectivity of the VAT with the right pre-SMA and the inferior frontal gyrus. 59 The opposing results from paradigms assessing global versus selective inhibition capacities support the conceptual and behavioural dissociation of two distinct forms of response inhibition. 60

Improved antisaccade latency may be an off-target effect
A decreasing effect of STN-DBS on antisaccade latency has been to date the most consistent finding. 24,50,[61][62][63] Of note, decreased response times (in absence of a simultaneous increase of errors) are equivalent to a relative normalization considering that antisaccade latency is typically increased in Parkinson's disease compared with healthy individuals. 24 Visualization of connected fibre tracts revealed that stimulation of fibre tracts passing by the STN laterally predicted latency decrease, while current delivered at fibres traversing the STN caused an opposite effect. It can thus be suggested that DBS-induced latency reduction may be rather driven by modulation of cortical projections bypassing the STN than an effect of modulating neuronal activity in the STN itself. A similar effect has been noted for DBS of the anterior limb of the internal capsule in individuals treated for depression or obsessive-compulsive disorder. 51 Here, stimulation of fibres of the anterior internal capsule enhanced cognitive control capacity supporting the hypothesis that DBS effects may be exerted via long-range modulation of cortical projections. 51 The clear distinction of negatively and positively correlated discriminative fibres on the level of the STN disappeared at the cortex level as the fibres tended to convergently project onto the same frontal regions. Corticotectal and corticopontine tracts connecting the prefrontal oculomotor regions with the superior colliculus and brainstem gaze control centres are located close to the lateral antero-superior border of the STN. 64 Modulation of these fibres via current spread may facilitate the generation of voluntary saccades without causing the sustained lateral fixation observed as a side effect with ill-positioned leads or high stimulation amplitudes. 65 Besides these direct projections, input from the cortical oculomotor control regions reaches the superior colliculus via the direct, indirect and hyperdirect basal ganglia pathways. 66 As such, it seems that the DBS effect is dependent on whether the fibres are involved in basal ganglia pathways or directly project onto down-stream gaze control regions.

Limitations
First, the parcellation of the STN into its subregions has been achieved using an atlas-based approach which does not account for any individual anatomical deviations. Furthermore, the functional division of the STN into two distinct region poses an oversimplification of the actual connectivity patterns emerging between frontal cortices and the STN. While there is indeed a dorsolateral-ventromedial gradient from preferentially motor to cognitive and limbic inputs, convergence of different cortical projections within the entire STN is large and without strict borders between motor and non-motor subregions. 13,67 Still, the subdivision into distinct regions has been proven to be a useful model of the actual anatomical conditions when studying DBS effects. 12,18 Secondly, the stimulation settings of some subjects had been optimized using imaging-guided approaches. 68 Accordingly, the VAT were predominantly localized within the motor subregion of the STN. Given potential relationships between saccade alterations and stimulation of structures outside the STN as suggested by our results, further investigations in patients with suboptimal lead or VAT locations may, in fact, be helpful to confirm our findings.
Thirdly, we cannot account for individual differences in structural connectivity between participants using a normative connectome. Relying on the assumption of similar connectivity profiles across participants is a clear limitation, although this approach has been used and validated in studies on DBS effects before. 47,59 Normative connectomes are based averaged highquality data sets of large numbers of participants, resulting in high signal-to-noise levels. Furthermore, lacking preoperative patient-specific connectivity data, a connectivity analysis would have otherwise been impossible in this study. While the subjects included in the PPMI dataset did not differ from our cohort regarding age or sex, disease stage might have been more advanced in our participants since PPMI aimed towards recruitment of early-stage Parkinson's disease. 45 The sample size is small, and generalizability of our results may be limited. Since DBS-off and DBS-on conditions were recorded on the same day with a relatively short wash-out period in between, carry-over effects into the DBS-off condition cannot be completely excluded.
All participants were recorded after withdrawal of their regular dose of dopamine replacement therapy which might be considered a strength of the study since it excludes effects of dopaminergic medication on the results to a large extent (long lasting effects > 12 h cannot be entirely excluded). On the other hand, previous evidence suggests differential effects of DBS on antisaccade performance dependent on medication state {Citation}. Hence, our findings may be limited to the 'off' medication state.

Conclusions and clinical implications
We confirmed previous studies 18,19 that stimulation of the non-motor, i.e. associative and limbic subregions of the STN can deter cognitive processes, here response inhibition. As discussed above, this may apply particularly in scenarios in which selective inhibition of one reflexive response is required to allow the selection of another voluntary action. In real life, we constantly apply selective inhibition so that Parkinson's disease-patients with impulse control disorders may particularly suffer from their reduced ability. 69 Additional impairment of response inhibition induced by STN-DBS may potentiate this tendency postoperatively, so that most centres include screening in for impulse control disorders in their preoperative screening. Our results lend credence to the idea that stimulation of associative-limbic subregions of the STN should be avoided, especially in patients with risk factors for impulse control disorders. With the increasing capacity of steering VAT with modern leads, actively avoiding a current spread into the ventromedial aspects of the (right) STN while retaining optimal control over motor symptoms may become feasible in more patients, even when leads are suboptimally located.
Our results regarding improved antisaccade latency with stimulation of a distinct set of fibres passing the STN laterally provide first preliminary evidence that STN-DBS of may have enhancing effects on voluntary eye movement control through modulation of prefrontal projections. If this finding is replicable in future studies on response inhibition, adapting DBS programs using patient-specific visualization of VAT and stimulated fibre tracts may not only be useful for avoiding side effects and increasing the therapeutic window but may even exert beneficial effects on cognitive control.

Supplementary material
Supplementary material is available at Brain Communications online.

Funding
This study was supported by the SUCCESS (Supporting Careers of Clinicians Seeking Science) program of Philipps-University Marburg (JW).

Competing interests
D.P. and L.T. received payments as consultants for Boston Scientific. L.T. received honoraria as a speaker on symposia sponsored by Boston Scientific and Medtronic. J.W., A.S., C.S. and K.S. have nothing to report.